Process for the preparation of pyrocatechols

ABSTRACT

The preparation of lower alkyl substituted pyrocatechol compounds by reacting a substituted phenolic ketone with an aqueous alkali metal carbonate-hydrogen peroxide solution. The pyrocatechol compounds are useful as intermediates in the preparation of pharmaceutically active compounds such as antibacterials, coccidiostats, and antioxidants.

United States Patent [191 Gurien et al. Oct. 9, 1973 [54] PROCESS FOR THE PREPARATION OF 2,644,014 6/1953 Saunders 260/621 G PYROCATECHOLS 2,395,638 2/1946 Milas 260/621 0 x 3,354,221 11/1967 Sandis et a] 260/621 R X [75] Inventors: Harvey Gurien, Maplewood; Albert Israel Rachlin, both of Verona, NJ, [73] Assignee: Hoffmann-La Roche lnc., Nutley, Primary Ziwer NJ. Assistant ExammerNorman A. Morgenstern Attorney-Samuel L. Welt, Jon S. Saxe, Bernard S. [22] Filed: June 22, 1970 Appl. No.: 48,476

Related U.S. Application Data Continuation-impart of Ser. No, 730,920, May 21, 1968, abandoned.

U.S. Cl 260/621 R, 260/592, 260/613 D, I

7 260/625 Int. Cl. C07c 37/00 Field of Search 260/593, 621 R, 625

Leon, George M. Gould and William H. Epstein [57] ABSTRACT The preparation of lower alkyl substituted pyrocatech01 compounds by reacting a substituted phenolic ketone with an aqueous alkali metal carbonate-hydrogen peroxide solution.' The pyrocatechol compounds are useful as intermediates in the preparation of pharmaceutically active compounds such as anti-bacterials, c'occidiostats, and antioxidants.

4 Claims, No Drawings 1 PROCESS FOR THE PREPARATION or PYROCATECHOLS CROSS-REFERENCES This application is a continuation-in-part of copending application, Ser. No. 730,920, filed by Harvey Gurien and Albert Israel Rachlin on May 21, 1968 now abandoned.

BACKGROUND OF THE INVENTION This invention relates to a new process for preparing known compounds, namely, pyrocatechols of the formula Formula I1 ration of pyrocatechol compounds o f'Forrnula I, no"

heretofore known method produces the pyrocatech'ols in high yields. For example, one method which has been reported in the synthesis of 3,4- dimethylpyrocatechol from 2,3-dimethyl-6'-' acetylphenol using an alkali sodium hydroxide hydrogen peroxide solution. This method, however, suffers from the disadvantage in that the yields are low, i.e. 2.5 percent. See Baker et al., J. Chem. Soc. 1953, 1615. Another method which has been reported is the synthesis of 3,4-dimethoxy-pyrocatechol from 2,3-dimethoxy- 6-acetylphenol utilizing an alkali quarternaryihydroxide hydrogen peroxide solution. This method is similarly disadvantageous in that the yields are low, Le. 25 percent. See Baker et al., J. Chem. Soc. 1934", 1681. With such yields, meither process has been proven to be of commercial interest. I

Accordingly, it is of great interest to obtain the pyrocatechol compounds of Formula l by a commercially economic prosess in generally high yields so as to facilitate their use as intermediates for pharmaceutically active compounds.

SUMMARY OF THE INVENTION The pyrocatechol compounds of Formula I can be produced in generally high yields from a substituted phenolic ketone utilizing the process of the present invention.

Specifically, the pyrocatechol compounds of Formula I can be prepared by reacting a substituted phenolic ketone of the formula COR OH 5H 1 O R are s m wherein R is-as above defined, and

R is lower alkyl, with an aqueous alkali metal carbonate-hydrogen peroxide solution. This reaction'effects replacement of the acyl group to yield the desired pyrocatechol compounds of Formula I.

As used herein, lower alkyl comprehends alkyl groups containing anywhere fromone to six carbon atoms, e.g., methyl, ethyl, N-propyl, butyl, and the like.

As noted above, R and R can each represent a lower alkyl group. In a preferred embodiment, R and R will each represent a methyl group.

As noted, the: compounds encompassed by Formula I can be" produced by'reacting a compound of Formula II with an aqueous alkaline hydrogen peroxide solution.

The reaction issuitably conducted at a temperature of from about 15 to about 40C. utilizing as the alkali, a carbonate compound such as sodium carbonate, potassium carbonate or lithium carbonate. A preferred embodiment utilizes sodium carbonate. The reaction is suitably in'itiatedat room temperature (i.e. from about 20 to 25C.) and thereafter maintained at from about 25 to about 40C. Preferably, the reaction is conducted at a temperature of from about 30 to about 35C. in the presence of a lower alkanol (e.g., methanol, ethanol, isopropanol, N-propanol, butanol, etc.).

In a preferred embodiment, the reaction is conducted in the presence of ethanol.-

The reactionalso suitably proceeds utilizing the compounds of Formula II in a molar ratio of from about 2:1 to about 2:3 per mol of carbonate compound. Likewise, the molar ratio of hydrogen peroxide to carbonate compound is suitably from about 1:1 to about 3:1 preferably, about 2:1.

Varying the molar proportions of the quantities of the starting materials (i.e. compounds of Formula II) to the carbonate compound and hydrogen peroxide to the carbonate compound will, of course, affect the yield of they resultant product. Good yields of pyrocatechol compounds ofFormulaI are obtained when, for example, a compound of Formula II to the carbonate compound is present in a molar ratio of 1:1 and the ratio of hydrogen peroxide to the carbonate compound is 2:1. Excellent yields of pyrocatechol compounds are obtained when; for example, a compound of Formula II to the carbonate compound is present in a molar ratio of 1:1 and the ratio of hydrogen peroxide to the carbonate compounds is 2:1. In a preferred embodiment,

With respect to the acylating agents utilized in the first step of the multi-step process for preparing the starting material of Formula ll, suitable acylating agents include the anhydrides and acid chlorides of the aliphatic acids having from 2 to 6 carbon atoms; preferably 2 to 3 carbon atoms. In a preferred embodiment, the acylating agent will bev acetic anhydride or acetyl chloride.

Although inert solvents may be utilized in the practice of the above initial step of the multi-step process, it is more desirable to employ an excess of the acylating agent to serve as the reaction medium. In a particularly preferred embodiment, the aforesaid initial reaction is conducted at the reflux, temperature of the acylating agent. However, lower or higher temperatures may be employed as desired.

The resulting mixture of compounds corresponding to Formula Illa and lllb above wherein R is lower alkyl having from 1 to 6 carbon atoms, is next treated with a Lewis acid catalyst to effect a rearrangement to the corresponding compounds of Formula Ila and [lb above. In a preferred embodiment, this reaction is conducted in the absence of a solvent and at a temperature in excess of 165C. This elevated temperature is necessary order order to get the rearrangement to proceed into the desired position, i.e., ortho to the original acyl group. Examples of Lewis acids which may be used in the aforesaid rearrangement include aluminum chlo wherein R is as above defined and Alk is a lower 'alkyl group, by alkylation with an alkylating agent in a manner well Formula I known in the art. Suitable alkylating agents include lower alkyl sulfates, e.g., methyl iodide, dimethyl sulfate, ethyl iodide, etc.

The present invention may be more clearly understood by reference to the following examples. All temperatures disclosed therein are in degrees centigrade.

Example 1 Preparation of 3,4-dihydroxytoluene' Into-a l2-liter three-neck flask, equipped with stirrer, thermometer, take-off condenser and under nitrogen was placed 540.5 g. of mixed meta and para cresols, 91 percent pure, equivalent to 492 g. (4.55 moles) of percent material. to this was added 5 80 g. (5.60 moles, 537 ml.) of 98 percent acetic anhydride, and the resulting mixture was stirred and refluxed (oil bath) for 4 hours. The bath temperature was then slowly raised to 200, and the excess acetic anhydride and formed acetic acid were distilled. The internal temperature was then adjusted and maintained at 1l0-l30 and 900g. of anhydrous aluminum chloride was added with mixing in portions with cooling. Upon completion of the addition of the aluminum chloride, the internal temperature was raised to 165. (The reaction mixture may bcome difficult to stir between and 165, but is fluid at 165, and stirring is resumed.) The mixture was .stirred at 165 for 1 hour, cooled to (internal temperature), and 2.38 l. of 4 N hydrochloric acid was added slowly while cooling to 9095. The mixture was then stirred for 1 hour at 80-90, and then for 3 hours at room temperature. The organic layer was separated, and the aqueous phase was extracted with six 250 m1. portions of toluene. The organic layers were combined, concentrated at reduced pressure to remove the solvent, the residual oil was dissolved in 3.75 1. of ehtanol and transferred to a 22-liter, 3-neck flask equipped with stirrer, condenser and thermometer. To the stirred solution was added, in portions, an alkaline hydrogen peroxide solution previously prepared from 625 ml. of 30 percent hydrogen peroxide (6.12 moles) in 1.75 l. of water and mixed with a solution of carbonate 580 g. of sodium carbonate (5.47 moles) in 3.75 l. of water at 15 and the whole cooled and stored at 05 while awaiting addition. During the addition of the alkaline hydrogen peroxide, the temperature slowly rose, and was kept at 303 3 by means of external cooling. Upon completion of the addition (45-60 min.), the mixture was stirred for 2 hours at 33-36. Sodium bisulfate (50.2 g.) was added portion-wise to destroy the excess hydrogen peroxide as determined by a starch iodide test. The reaction mixutre was cooled while being acidified to pH 2 with 320 ml. of concentrated sulfuric acid and then diluted with 6 l. of water to dissolve the salts formed. The mixture was then extracted with four 500 ml. portions of hexane and then with 12 600 ml. portions of ether. The combined ether extracts were dried over sodium sulfate and concentrated. The residual oil was distilled at reduced pressure. After collection of a forerun (b.p. 381l5/20-l9 mm.), the main fraction distilled at 149-157/17-20 mm., yielding crude 3.4- dihydroxytoluene, m.p. 56.459.9. Recrystallization was effected from 2.42 l. of 1:1 benzene-hexane. The solution was brought to the boil, cooled slightly, 20.4 g. Norit A was added and the mixture was again brought to the boil and filtered hot. When the cooling filtrate became trubid, it was seeded and allowed to cool with stirring until well crystallized. It was then refrigerated overnight. Upon filtration and washing with 282 ml cold 1:1 benzene-hexane and drying in vacuum at 30, there was obtained product of m.p. 6466. Removal of the solvent from from the mother liquor gave additional crude product which was dissolved in 550 ml. of 1:1 benzene-hexane at room-temperature, seeded and refrigerated overnight. Upon filtration, washing with 100 ml. 1:1 benzene-hexane (cold) and drying in vacuum at 30, there was obtained an additional crop of product of m.p. 6466. Yield: 90.8 percent.

EXAMPLE 2 mole) of 3,4-dihydroxytoluene (distilled, unrecrystal- Into a 2-liter five-neck flask equipped with stirrer,

thermometer, pl-l electrode connected to a pH meter, condenser, two dropping funnels at either side of the flask and under nitrogen were placed 100 g. (0.805 mole) of 3,4-dihydroxytoluene (distilled and recrystallized) and 1 l. of water. One dropping funnel was charged with 290 ml. (2.90 mole) of 10 N sodium hydroxide and the other with 304.5 g. (2.42 mole, 229.5 ml.) of dimethyl sulfate. The internal temperature was adjusted to -35, and during the course of addition of the reagents, the temperature was maintained in that range by occasional cooling with an external ice bath.

The pH was next adjusted to 11.5 by the addition of a portion of the alkali, followed by the addition of the dimethyl sulfate over a period of 1 hour. Concurrently, the alkali was added at such a rate as to maintain the pH at 11-1 1.5. An additional hour was required to complete the addition of the alkali, while maintaining the indicated pl-l, after which the pH electrode was removed, the reaction mixture was heated to 95 for 10 minutes, and then cooled to room temperature with an external ice bath. The organic phase was separated and the aqueous phaseextracted with six 200 ml. portions of dichloromethane. The combined organic phase was washed with 200 ml. of 1 N sodium hydroxide, 200 ml. of water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuum to give a light yellow oil. Upon distillation there was obtained 3,4- dimethoxytoluene, b.p. l06.5-l10/l2.5 mm, m.p. 2l.2; n 1.5268. Yield: 96.5 percent of theory form 3,4-dihydroxytoluene.

B. From distilled, dihydroxytoluene lnto a 500-ml., five-neck flask equipped with stirrer, thermometer, pl-l electrode and meter, two dropping unrecrystallized 3,

lized of 98.0 percent purity), 244 ml. of water, and the temperature was brought to 3035. Into the dropping funnels (arranged to avoid prior mixing as in A above) were placed ml. of 10 N sodium hydroxide and 56.5 ml. (0.584 mole) of dimethyl sulfate. A quantity of the alkali was added to pH ll-l 1.5. The dimethyl sulfate and sodium hydroxide were then added dropwise and concurrently at rates such that the temperature and pH were maintained at 3035 and 11-l1.5, respectively.

The addition was complete in 20 minutes. After stirring at 3035 for an additional 45 minutes, the pH electrode was removed and the reaction mixture was heated to while the residual sodium hydroxide was added (IO-15 minutes) and held at this temperature for 10 minutes. The flask was next cooled externally to room temperature. The organic phase was separated and the aqueous phase was extracted with four 50 ml. portions of methylene chloride. The combined organic extracts were washed with 50ml. of l N sodium hydroxide and 50 ml. of water. After drying over anhydrous magnesium sulfate, the organic phase was concentrated and distilled to give product of b.p. l12/114/18mm.n,, 1.5307.

Yield: 87.5%

EXAMPLE 3 Preparation of 3,4-diethoxytoluene Into a 250-ml., five-neck flask equipped with stirrer, thermometer, two dropping funnels and pH meter, under nitrogen were placed 12.4 g. (0.10 mole) of 3,4- dihydroxytoluene (distilled, recrystallized) and ml. of water. The dropping funnels were charged with 61.6 g. (0.40 mole) of freshly distilled diethyl sulfate and 48.0 ml. of 10 N (0.48 mole) sodium hydroxide, respectively. While maintaining the temperature at 30-35, the sodium hydroxide and diethyl sulfate were concurrently added dropwise at a rate such that the pH was maintained at 11.0-11.5; The addition ofthe diethyl sulfate required 30 minutes. The pH meter was removed and the mixture was heated to 95 as the remainder of the alkali was added. It was held at 95 for 10 minutes and then cooled to room temperature. The organic layer was separated and the aqueous phase was extracted with six 25 ml. portions of methylene chloride. The combined organic phases were washed with 25 ml. of 1 N sodium hydroxide and then with 25 ml. of water. After drying over anhydrous magnesium sulfate and removal of the solvent, the crude porduct weighed 17.6 g. Upon distillation, 16.6 g. of 3,4- diethoxytoluene was obtained, b.p. l091 l4/8.9 mm.

We claim:

1. A process for the preparation of a dihydroxy compound of the formula:

, wherein R is lower alkyl; comprising reacting at a temperature of from 15 centigrade to 40 centigrade, a ketone of the formula:

| I on com wherein R, is lower alkyl', and R is as above; with an aqueous solution containing an alkali metal carbonate and a hydrogen peroxide wherein the mole ratio of said ketone to the alkali metal carbonate is carbonate is sodium carbonate. 

2. The process of claim 1 wherein R is methyl.
 3. The process of claim 1 wherein the reaction proceeds in the presence of a lower alkanol.
 4. The process of claim 1 wherein the alkaline metal carbonate is sodium carbonate. 